Morpholinium trifluoroacetate-catalyzed aldol condensation of acetone with both aromatic and aliphatic aldehydes

Article abstract of DOI:10.1002/adsc.200900902

We report a highly efficient, general and practical method for the aldol condensation of acetone with aromatic and aliphatic aldehydes, using morpholinium trifluoroacetate as a catalyst.

Full text of DOI:10.1002/adsc.200900902

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DOI: 10.1002/adsc.200900902
Morpholinium Trifluoroacetate-Catalyzed Aldol Condensation of
Acetone with both Aromatic and Aliphatic Aldehydes
Kristina Zumbansen,a Arno Dçhring,a and Benjamin Lista,*
a
Max-Planck-Institut fꢀr Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr, Germany
Fax : (+49)-208-306-2999; phone: (+49)-208-306-2410; e-mail: list@mpi-muelheim.mpg.de
Received: December 28, 2009; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900902.
Abstract: We report a highly efficient, general and
practical method for the aldol condensation of ace-
tone with aromatic and aliphatic aldehydes, using
morpholinium trifluoroacetate as a catalyst.
for the aldol condensation, different Knoevenagel-
type secondary amine salts were studied in two reac-
tions of acetone, one with benzaldehyde (2a) and the
other one with the more challenging n-octanal (3a).
Piperidinium acetate (1a) [pKA (piperidine)
11.1],[11] thiomorpholinium acetate (1c) [pKA (thio-
morpholine) 9.0],[11] and morpholinium trifluoroace-
tate (1e) [pKA (morpholine) 8.4][11] catalyzed the
aldol condensation of benzaldehyde smoothly
(Table 1, entries 1, 3 and 5) whereas piperidinium tri-
fluoroacetate (1b) and morpholinium hydrochloride
Keywords: aldehydes; aldol condensation; amine
salts; enones; organocatalysis
The versatile utility of a,b-unsaturated methyl ke- (1d) suffered from low reactivity (entries 2 and 4).
tones in organic synthesis continues to draw signifi- With dibenzylammonium trifluoroacetate (1f),[12]
cant interest in developing new methods for their syn- large amounts of by-product were obtained.
thesis.[1] Such enones are generally obtained via aldol
Aliphatic aldehyde 3a usually gave full conversion
condensation of acetone with aldehydes.[2] This reac- in the condensation reaction within a few hours but
tion can be performed with acidic or basic catalysts. the selectivities of these reactions varied significantly.
However, oligomerization and self-aldol condensation Among others, self-aldol condensation of the alde-
products of acetone and of aliphatic aldehydes are hyde and double condensation of acetone could be
often formed as by-products. In addition, the reaction observed as side reactions. Remarkably, morpholine,
can frequently not be stopped after the first conden- having the lowest pKA among the cyclic amines, in
sation reaction and a second reaction at the other combination with trifluoroacetic acid (1e), turned out
methyl group can occur. Due to these problems sever- to give the best results not only with benzaldehyde
al alternative catalyst systems were developed includ- but also with octanal. Surprisingly, this particular
ing zeolites,[3] ionic liquids,[4] amines and amine salts,[5] amine salt seems to have been studied only once
as well as metal and organometallic catalysts.[6] These before as catalyst and in a different reaction.[13]
methods often suffer from a narrow substrate scope
Several aromatic aldehydes were studied next using
and modest functional group tolerance. Lewis acid- optimized reaction conditions (Table 2).[15] Electron-
mediated tandem Mukaiyama aldol–dehydration reac- rich and electron-poor aldehydes as well as o-substi-
tions have also been developed but possess a signifi- tuted aldehydes were converted into the correspond-
cantly reduced step and atom economy.[7] Similarly, ing enones in excellent yields (87 to 99%). In general
Wittig and Horner–Wadsworth–Emmons reaction var- electron-poor aldehydes reacted faster. Functional-
iations, which are generally useful in principle, suffer ized aldehydes bearing hydroxy, ether, ester, amine,
from stoichiometric by-products.[8,9,10] Here we report amide, carboxylic acid and cyano moieties were readi-
a strikingly simple, general, and highly selective aldol ly transformed into the corresponding condensation
condensation variant of acetone with both aromatic products (entries 3 to 10, 12 and 14 to 15). Heteroaro-
and aliphatic aldehydes that is catalyzed by morpholi- matic aldehydes are also processed in high yields (en-
nium trifluoroacetate.
tries 15 and 16).
Since we have found secondary amine salts to be
Remarkably, under almost identical conditions, the
generally superior to primary amine salts as catalysts much more challenging enolizable aliphatic aldehydes
Adv. Synth. Catal. 2010, 352, 1135 – 1138
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Kristina Zumbansen et al.
Table 2. Aldol condensation of aromatic aldehydes.[a]
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Table 1. Screening of secondary amine salt catalysts.[a]
Entry
2
Ar
4
Yield [%][b]
Entry Catalyst
1
Aldehyde t
Conversion Selectivity
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
C6H5
p-CF3-C6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
96
95
98
99
97
96
94
90
96
93[c]
91
94[c]
95
91
92
94
95
87
94
95
92
95
[h] [%][b]
[%][b]
p-NO2-C6H4
p-HO-C6H4
p-MeCO2-C6H4
p-Me2N-C6H4
p-MeCONH-C6H4
p-HCO2-C6H4
p-CN-C6H4
2a
3a
24 >99
98
95
46
2
3
1a
3
2a
3a
26 82
94
98
57
4
4
9
1b
10
11
12
13
14
15
16
17
18
19
20
21
22
p-CHO-C6H4
o-Me-C6H4
m-CHO-C6H4
3,5-Me-C6H3
3,5-(CF3)2-C6H3
3,5-(MeO)2-C6H3
3-MeO-5-HO-C6H3
2-thienyl
3-pyridinyl
1-naphthyl
2-naphthyl
9-anthracenyl
1-pyrenyl
5
2a
3a
26 97
98
>99
73
6
3
1c
7
2a
3a
26 33
22 68
96
44
8
1d
2s
2t
2u
2v
4s
4t
4u
4v
9
2a
3a
20 >99
3
>99
10
>99
85
1e
[a]
Reaction conditions: 5 mmol 2, 20 mol% 1e, 12.5 mL ace-
tone, 758C, 12–84 h in a sealed vial.[14]
Isolated yield.
[b]
[c]
11
2a
3a
26 93
>99
62
33
Condensation occurred on both aldehyde functions.
12
1f
3
[a]
Reaction conditions using 2a: 5 mmol 2a, 20 mol% 1e,
12.5 mL acetone, 758C in a sealed vial; reaction condi-
tions using 3a: 5 mmol 3a, 20 mol% 1e, 5 mL acetone,
758C in a sealed vial.
Table 3. Aldol condensation of aliphatic aldehydes.[a]
[b]
Determined by GC.
3 were also processed to give the corresponding
enones 6 in good to high yields in usually short reac-
tion times (Table 3). Again, functional groups includ-
ing a silyl ether and an ester are well tolerated (en-
tries 3 and 4). Moreover, several a-branched and
linear aldehydes reacted smoothly and gave the de-
sired products in high yields (entries 8–11). As in the
case of the aromatic products (Table 2), the E/Z ratio
of the enone double bond in all products was >95:5
(from NMR).
To demonstrate the practicality of this process, our
protocol was applied to a 45 g (0.35 mol) scale reac-
tion of octanal with acetone following distillation to
furnish condensation product 6a in 81% isolated
yield.[16]
Entry
3
R
t [h]
6
Yield [%][b]
1
2
3
4
5
6
7
8
3a n-heptyl
3b cyclohexyl
3c TBSO-(CH2)3
3
24
2
1
3
2
3
7
3
6a 80
6b 81
6c 70
6d 80
6e 82
6f 79
6g 49[c]
6h 39[c]
6i 85
6j 73
3d EtO2C
(CH2)4
3e C6H5-(CH2)2
3f C6H5-(CH)2
3g t-Bu-CH2
3h
(CH3)
G
9
10
11
3i 2-furyl-(CH)
3j cyclohex-1-enyl
3k t-butyl
R
48
216 6k 30[c]
[a]
Reaction conditions: 5 mmol 3, 20 mol% 1e, 5 mL ace-
tone, 758C in a sealed vial.[14]
Isolated yield after column chromatography.
Low yield due to the volatility of the product.
[b]
[c]
An example illustrating the potential applicability
of our methodology in cascade sequences is shown in
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Adv. Synth. Catal. 2010, 352, 1135 – 1138

Morpholinium Trifluoroacetate-Catalyzed Aldol Condensation of Acetone
Scheme 1. One-pot synthesis of raspberry ketone.
General Procedure for the Aldol Condensation of
Aromatic Aldehydes 2
Scheme 1. First subjecting p-hydroxybenzaldehyde to
our morpholinium trifluoroacetate-catalyzed aldoliza-
tion with acetone, following a transfer hydrogenation
with Hantzsch ester 8 that is accelerated by the same
catalyst,[13] gave raspberry ketone (7), the primary
aroma compound of red raspberries. Raspberry
ketone is an important industrial product with anti-
fungal and antiobesity activities.[17]
We are currently investigating whether the reaction
proceeds via an aldol or Mannich mechanism (possi-
bly involving iminium ion and enamine catalysis).[18,19]
Kinetic studies of the reaction of 4-hydroxybenzalde-
hyde with acetone suggest a first order dependency
on the catalyst concentration (see Supporting Infor-
mation). In preliminary mass spectrometry experi-
ments, depending on the substrate, both Mannich and
in certain cases aldol intermediates have been detect-
ed.[20] The mechanistic details of this reaction, after
further experimentation, will be published in due
course.
In summary, we have developed a practical, high
yielding, and atom economic aldol condensation of
acetone with aromatic and aliphatic aldehydes. The
easily available catalyst, high selectivity, and function-
al group tolerance should make this a valuable proce-
dure. In addition, an aldol condensation–transfer hy-
drogenation sequence has been developed to give the
corresponding saturated ketone in good yields. Stud-
ies on the exact mechanism of the reaction are ongo-
ing.
To a solution of aldehyde 2 (5 mmol) in acetone (12.5 mL)
was added amine salt 1e (1 mmol, 201.14 mg). The reaction
mixture was stirred at 758C in a sealed vial. After the men-
tioned time (see Table 2) the reaction mixture was cooled to
room temperature, saturated NaHCO3 solution and ethyl
acetate were added. After phase separation the aqueous
phase was extracted three times with ethyl acetate and the
organic layer was dried over sodium sulfate and concentrat-
ed under vacuum to give mostly analytical pure products. If
necessary the crude product was purified by coloumn chro-
matography (ethyl acetate/hexane).
General Procedure for the Aldol Condensation of
Aliphatic Aldehydes 3
To a solution of aldehyde 3 (3 mmol) in acetone (3 mL) was
added amine salt 1e (0.6 mmol, 120.68 mg). The reaction
mixture was stirred at 758C in a sealed vial. After the speci-
fied time (see Table 3), the reaction mixture was cooled to
room temperature and saturated NaHCO3 solution or buffer
solution (pH 7) and diethyl ether were added. After phase
separation the aqueous phase was extracted three times
with diethyl ether and the organic layer was dried over
sodium sulfate and concentrated under reduced pressure.
The crude product was purified by column chromatography
(diethyl ether/pentane or dichloromethane/pentane).
Raspberry Ketone (7)
To a solution of aldehyde 2d (3 mmol) in acetone (7.5 mL)
was added amine salt 1e (0.6 mmol, 120.7 mg). The reaction
mixture was stirred at 758C in a sealed vial. After 12 h the
acetone was removed under vacuum, Hantzsch ester (8)
(3.6 mmol, 911.9 mg, 1.2 equiv.) and THF (10 mL) were
added under argon and the mixture was stirred at 608C for
12 h. After cooling to room temperature 1M HCl solution
and dichloromethane were added and the aqueous phase
was extracted three times with dichloromethane. The organ-
ic phase was dried over sodium sulfate and concentrated
under vacuum. Purification of the crude product by column
chromatography (ethyl acetate/hexane 1/3) afforded 7 as a
Experimental Section
General Procedure for the Preparation of Catalysts 1
To a solution of amine (10 mmol) in diethyl ether (20 mL) a
solution of the corresponding acid (11 mmol) in diethyl
ether/n-pentane (10 mL) was added slowly at 08C. After 1 h
the reaction was allowed to warm up to room temperature
and the white precipitate was filtered under argon and
washed with diethyl ether and pentane to afford the clean
amine salt.
1
yellowish solid; yield: 392.5 mg (2.4 mmol, 80%). H NMR
(400 MHz, CDCl3): d=7.03 (d, 2H, J=8.5 Hz), 6.75 (d, 2H,
J=8.5 Hz), 5.53 (br s, 1H), 2.82 (t, 2H, J=6.8 Hz), 2.73 (t,
2H, J=6.8 Hz), 2.14 (s, 3H); 13C NMR (125 MHz, CDCl3):
d=209.3, 154.2, 132.8, 129.48, 115.5, 45.6, 30.3, 29.0; MS
(EI): m/z (%)=164 (60) [M]+, 121 (14) [C8H9O]+, 107 (100)
Adv. Synth. Catal. 2010, 352, 1135 – 1138
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Kristina Zumbansen et al.
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[C7H7O]+, 43 (23) [C2H3O]+; HR-MS (EI-MS): m/z=
164.083603, calcd. for C10H12O2: 164.083733.
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Acknowledgements
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[14] Performing the reaction under reflux conditions did not
diminish the selectivity and the yield, but led to slightly
longer reaction times.
We thank our MS Department, Niels Sadlowski, Sonja
Pullen, Camila Dçhring, Jung Woon Yang, and Hyeong Bin
Jang for technical assistance. Generous support by the Max-
Planck-Society, the Deutsche Forschungsgemeinschaft (SPP
1179, Organokatalyse) and the Fonds der Chemischen Indus-
trie is gratefully acknowledged.
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Adv. Synth. Catal. 2010, 352, 1135 – 1138